ABSTRACT The use of exogenous hormones to treat the neurological symptoms associated with menopause as well as diseases of aging such as Alzheimer's disease (AD) is controversial. This controversy arose from several clinical trials including the Women's Health Initiative (WHI) memory study (WHIMS), the WHI study of cognitive aging (WHISCA), the WHI study of memory in younger women (WHIMSY), Early vs Late Intervention Treatment with Estrogen (ELITE) where menopausal hormone therapy (HT) either did not prevent dementia, or increased dementia and adverse cognitive effects. Collectively, these results of these studies suggest that HT may be effective if used within a critical window around menopause but not in in older women. The type of MT and route of exposure (i.e. oral conjugated equine estrogen [oCEE] vs. transdermal E2 [tE2]) are also important and studies such as the Kronos Early Estrogen Prevention Study (KEEPS), a double blind randomized clinical trial, have investigated effects of these MT on cognitive when given within 3 years of the onset of menopause. Variation in responses to HT may be related to pharmacokinetics and bioavailability associated with administering an exogenous estrogen. For example, in the KEEPS cohort, genetic variants of two genes encoding two different proteins involved in estrogen metabolism and transport i.e. SULTA1 and SLCO1B1 respectively, were associated with severity of menopausal hot flashes. In this supplemental grant, the goal is to investigate genetic variation in women in the KEEPS continuation study, which aims to investigate the effects of HT and any correlations to AD, thirteen years after the administration of HT. The genetic analysis will be expanded to include additional genes involved in estrogen pharmacokinetics, as well as those encoding proteins involved in estrogen signaling/pharmacodynamic pathways, which may impact response to hormone therapy in relation to cognition and brain structure and function. The results from this study will lead to a better understanding of the impact of genetic variation in estrogen pharmacokinetic and pharmacodynamic pathways, provide insight to the controversy of HT for AD therapy, and lead the way to developing individualized treatment approaches to AD.